Individuals who experience traumatic brain injury (TBI) are at increased risk for developing dementia and parkinsonism later in life. Exposure to repetitive head impacts (RHI) from contact sports and military service is also associated with a tau-based neurodegeneration, chronic traumatic encephalopathy (CTE). Our small case studies indicate that the neuropathological substrate of TBI-related neurodegeneration is a heterogeneous condition with varying degrees of beta-amyloid (A), phosphorylated tau (ptau), pTDP-43, and alpha-synuclein pathologies that does not conform to conventional Alzheimer's disease (AD) or AD related dementias (ADRD). Our studies also suggest that other pathologies, including gray and white matter atrophy, vascular pathology, neuronal, axonal and myelin loss, astrocytosis, and neuroinflammation contribute to neurodegeneration after TBI and RHI. Moreover, it is increasingly recognized that the type, frequency and severity of TBI or RHI and other genetic and non-genetic factors exert striking influence on the long-term outcome. TBI and RHI have not been well studied in brain bank cohorts, subsequently, the contribution of TBI and RHI to AD, ADRD, CTE and other pathologies is not known. There is a critical unmet need to determine the relationship of TBI and RHI to AD, ADRD, CTE and other pathologies, to understand the neuropathological phenotype of TBI, to determine the prevalence of TBI-related neurodegeneration and CTE in brain bank cohorts, and to determine the relationship of TBI and RHI to cognitive decline and parkinsonism. To accomplish our goals, we will leverage the infrastructure of our successful Understanding Neurological Injury and Traumatic Encephalopathy (UNITE) study (U01NS086659, R01AG057902) and our collaboration with Mount Sinai (U01NS086625). We will harmonize 8 novel brain banks: 6 at Boston University (BU) and 2 at Icahn School of Medicine at Mount Sinai (ISMMS). In this proposal, we will examine the association of RHI and TBI with AD, ADRD, CTE neuropathology and other pathologies and investigate genetic and non-genetic modifiers of these effects. The overarching hypotheses are: RHI and TBI will have distinct associations with AD, ADRD, CTE and other pathologies; these effects will be modified by genetic (e.g., APOE ?4, TMEM106b) and non-genetic factors (e.g., age of first exposure to RHI ) and TBI, age, cardiovascular disease, resistance, among other RHI/TBI characteristics and demographic, lifestyle, and medical histories ; and these pathologies will have direct associations with clinical outcomes of dementia and parkinsonism. This U54 will develop the largest brain donor cohort with well-characterized histories of RHI and TBI across the severity spectrum. This project will advance knowledge on the specific risks for the pathological development of AD, ADRD, CTE and other degenerative pathologies after RHI and TBI, establish the neuropathological features of TBI-related neurodegeneration, and determine the association of post-RHI and TBI neuropathologies with the clinical phenotypes of dementia and parkinsonism. This U54 proposal will lay the foundation for future strategies to intervene, prevent and treat TBI-related neurodegeneration and CTE.